JP2015051994A - Preparation process for macrolide antibacterial agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel macrolide antibacterial agent.SOLUTION: The present invention provides a process for the preparation of a compound of the formula, and pharmacologically acceptable salt, solvate and hydrate thereof.

Description

  The invention described herein relates to a process for preparing a macrolide antibacterial agent. Specifically, the present invention relates to intermediates and processes for preparing ketolides and other macrolides containing 1,2,3-triazole substituted side chains.

  The use of macrolides for various infectious diseases is widely known. Erythromycin was the first compound of its kind introduced in clinical practice. Since then, further macrolides, including ketolide compounds, have received much interest because of their ability to treat a wide variety of disease states. In particular, macrolides have become an important component of therapeutic methods for treating bacterial, protozoal and viral infections. In addition, macrolides are often used in patients with penicillin allergy.

  As an illustration of these widespread uses, macrolide compounds have been found to be effective for the treatment and prevention of infections caused by a wide range of bacterial and protozoal infections. They are also useful for infections of respiratory tract infections and soft tissue infections. Macrolide antibiotics have been found effective against β-hemolytic streptococci, pneumococci, staphylococci and enterococci. They have also been found effective against mycoplasma, mycobacteria, some rickettsias, and chlamydia.

  Macrolide compounds are characterized by the presence of large lactone rings, which are generally 14-, 15- or 16-membered macrocyclic lactones, which include deoxy sugars such as cladinose and desosamine. One or more saccharides may be bound. For example, erythromycin is a 14-membered macrolide compound that contains two sugar moieties. Spiramycin belongs to the second generation of macrolide compounds containing 16-membered rings. Third generation macrolide compounds include, for example, semi-synthetic derivatives of erythromycin A such as azithromycin and clarithromycin. In addition, ketolides have received much attention in recent years because of their acid stability and, most importantly, their superior activity with respect to microorganisms that are resistant to other macrolides. It represents a newer class of macrolide antibiotics. Like erythromycin, ketolides are 14-membered macrolide derivatives characterized by a keto group at the C-3 position (see Non-Patent Document 1). Several ketolide compounds are currently in clinical trials. However, telithromycin (see U.S. Patent No. 6,057,049) is the first compound in this family that has been approved for use.

  Liang et al. Describe a new series of compounds and their exemplary syntheses in US Pat. These new compounds show excellent activity with respect to a variety of pathogenic microorganisms, including those that have already shown resistance to current therapies. Specifically, Liang et al. Describe a plurality of compounds, including the following compounds of formula (I), and pharmaceutically acceptable salts, solvates and hydrates thereof:

（式中、
Ｒ^１は単糖類または多糖類であり；
Ａは、−ＣＨ_２−、−Ｃ（Ｏ）−、−Ｃ（Ｏ）Ｏ−、−Ｃ（Ｏ）ＮＨ−、−Ｓ（Ｏ）_２−、−Ｓ（Ｏ）_２ＮＨ−、または、−Ｃ（Ｏ）ＮＨＳ（Ｏ）_２−であり；
Ｂは−（ＣＨ_２）_ｎ−であって、式中、ｎは、０から１０までの整数であるか、あるいは、Ｂは、任意のアルケニル基またはアルキニル基を含有し得る、２個〜１０個の炭素の不飽和炭素鎖であり；
Ｃは、水素、ハロゲン、ヒドロキシ、アルキル、アラルキル、アルキルアリール、アルコキシ、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、アミノアリール、アルキルアミノアリール、アシル、アシルオキシ、スルホニル、尿素（ｕｒｅｙｌ、ウレイルともいう。以下に同じ。）およびカルバモイル（これらのそれぞれが任意に置換される）から、それぞれの場合において独立して選択される１個または２個の置換基を表し；
Ｖは、−Ｃ（Ｏ）−、−Ｃ（＝ＮＲ^１１）−、−ＣＨ（ＮＲ^１２Ｒ^１３）−または−Ｎ（Ｒ^１４）ＣＨ_２−であり；式中、Ｒ^１１はヒドロキシまたはアルコキシであり、Ｒ^１２およびＲ^１３はそれぞれが独立して、水素、ヒドロキシ、アルキル、アラルキル、アルキルアリール、アルコキシ、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、ジメチルアミノアルキル、アシル、スルホニル、尿素およびカルバモイルから選択され；かつ、Ｒ^１４は、水素、ヒドロキシ、アルキル、アラルキル、アルキルアリール、アルコキシ、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、ジメチルアミノアルキル、アシル、スルホニル、尿素またはカルバモイルであり；
Ｗは、水素、Ｆ、Ｃｌ、Ｂｒ、ＩまたはＯＨであり；かつ、
Ｘは水素であり；かつ、ＹはＯＲ^７であり；式中、Ｒ^７は、水素、アミノ糖またはハロ糖を含む単糖類もしくは二糖類、アルキル、アリール、ヘテロアリール、例えば４−ニトロフェニルアセチルおよび２−ピリジルアセチルなどのアシル、または−Ｃ（Ｏ）ＮＲ^８Ｒ^９であり、式中、Ｒ^８およびＲ^９はそれぞれが独立して、水素、ヒドロキシ、アルキル、アラルキル、アルキルアリール、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、ジメチルアミノアルキル、アシル、スルホニル、尿素およびカルバモイルから選択され；あるいは、ＸおよびＹは、結合する炭素と一緒になって、Ｃ＝Ｏを形成する）。

(Where
R ¹ is a monosaccharide or polysaccharide;
A represents —CH ₂ —, —C (O) —, —C (O) O—, —C (O) NH—, —S (O) ₂ —, —S (O) ₂ NH—, or -C (O) NHS (O) _2- ;
B is — (CH ₂ ) _n —, where n is an integer from 0 to 10, or B may contain any alkenyl or alkynyl group, 2-10 An unsaturated carbon chain of carbons;
C is hydrogen, halogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl, urea (ureyl, ureyl) The same below) and carbamoyl (each of which is optionally substituted) represents in each case one or two substituents independently selected;
V is —C (O) —, —C (═NR ¹¹ ) —, —CH (NR ¹² R ¹³ ) — or —N (R ¹⁴ ) CH ₂ —; where R ¹¹ is hydroxy or alkoxy R ¹² and R ¹³ are each independently hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, urea and Selected from carbamoyl; and R ¹⁴ is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, urea or carbamoyl;
W is hydrogen, F, Cl, Br, I or OH; and
X is hydrogen; and Y is OR ⁷ ; where R ⁷ is a monosaccharide or disaccharide containing hydrogen, amino sugar or halo sugar, alkyl, aryl, heteroaryl, eg 4-nitrophenylacetyl And acyl such as 2-pyridylacetyl, or —C (O) NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are each independently hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, heteroalkyl , Aryl, heteroaryl, heteroarylalkyl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl, urea and carbamoyl; or X and Y together with the carbons to which they are attached form C = O) .

  Specifically, 11-N-[[4- (3-aminophenyl) -1,2,3-triazol-1-yl] -butyl] -5-desosaminyl-2-fluoro-3-oxoerythronolide Compounds that are A, 11,12-cyclic carbamates are described by Liang et al.

  Because of the importance of these new compounds and other compounds that continue to be used to provide beneficial therapies for treating pathogenic microorganisms, alternative processes for preparing these compounds and There is a need for improved processes.

US Pat. No. 5,635,485 US Patent Application Publication No. 2006/0100164

Curr. Med. Chem. , “Anti-Infective Agents”, 1: 15-34 (2002).

  For example, the inventors have found that when using conventional synthesis of compounds of formula (I), side reactions occur and undesirable side products and impurities are formed. Such side reactions reduce the overall yield of the desired compound, and such side products and impurities can complicate the purification of the desired compound. There is herein a new process that may be advantageous in preparing compounds of formula (I) that can avoid such by-products and / or be purified to a higher level of purity. Is described.

（式中、
Ｒ^１は単糖類または多糖類であり；
Ａは、−ＣＨ_２−、−Ｃ（Ｏ）−、−Ｃ（Ｏ）Ｏ−、−Ｃ（Ｏ）ＮＨ−、−Ｓ（Ｏ）_２−、−Ｓ（Ｏ）_２ＮＨ−、または、−Ｃ（Ｏ）ＮＨＳ（Ｏ）_２−であり；
Ｂは−（ＣＨ_２）_ｎ−であって、式中、ｎは、０から１０までの整数であるか、あるいは、Ｂは、任意のアルケニル基またはアルキニル基を含有し得る、２個〜１０個の炭素の不飽和炭素鎖であり；
Ｃは、水素、ハロゲン、ヒドロキシ、アルキル、アラルキル、アルキルアリール、アルコキシ、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、アミノアリール、アルキルアミノアリール、アシル、アシルオキシ、スルホニル、尿素およびカルバモイル（これらのそれぞれが任意に置換される）から、それぞれの場合において独立して選択される１個または２個の置換基を表し；
Ｖは、−Ｃ（Ｏ）−、−Ｃ（＝ＮＲ^１１）−、−ＣＨ（ＮＲ^１２Ｒ^１３）−または−Ｎ（Ｒ^１４）ＣＨ_２−であり；式中、Ｒ^１１はヒドロキシまたはアルコキシであり、Ｒ^１２およびＲ^１３はそれぞれが独立して、水素、ヒドロキシ、アルキル、アラルキル、アルキルアリール、アルコキシ、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、ジメチルアミノアルキル、アシル、スルホニル、尿素およびカルバモイルからなる群から選択され；Ｒ^１４は、水素、ヒドロキシ、アルキル、アラルキル、アルキルアリール、アルコキシ、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、ジメチルアミノアルキル、アシル、スルホニル、尿素またはカルバモイルであり；
Ｗは、水素、Ｆ、Ｃｌ、Ｂｒ、ＩまたはＯＨであり；
Ｘは水素であり；かつ、ＹはＯＲ^７であり；式中、Ｒ^７は、水素、アミノ糖またはハロ糖を含む単糖類もしくは二糖類、アルキル、アリール、ヘテロアリール、例えば４−ニトロ−フェニルアセチルおよび２−ピリジルアセチルなどのアシル、または−Ｃ（Ｏ）ＮＲ^８Ｒ^９であり、式中、Ｒ^８およびＲ^９はそれぞれが独立して、水素、ヒドロキシ、アルキル、アラルキル、アルキルアリール、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、ジメチルアミノアルキル、アシル、スルホニル、尿素およびカルバモイルから選択され；あるいは、ＸおよびＹは、結合する炭素と一緒になって、Ｃ＝Ｏを形成する）。 In one exemplary embodiment of the invention, a process for preparing the following compounds of formula (I) and pharmaceutically acceptable salts, solvates and hydrates thereof is described:

(Where
R ¹ is a monosaccharide or polysaccharide;
A represents —CH ₂ —, —C (O) —, —C (O) O—, —C (O) NH—, —S (O) ₂ —, —S (O) ₂ NH—, or -C (O) NHS (O) _2- ;
B is — (CH ₂ ) _n —, where n is an integer from 0 to 10, or B may contain any alkenyl or alkynyl group, 2-10 An unsaturated carbon chain of carbons;
C is hydrogen, halogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl, urea and carbamoyl (each of these Represents one or two substituents independently selected in each case;
V is —C (O) —, —C (═NR ¹¹ ) —, —CH (NR ¹² R ¹³ ) — or —N (R ¹⁴ ) CH ₂ —; where R ¹¹ is hydroxy or alkoxy R ¹² and R ¹³ are each independently hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, urea and R ¹⁴ is selected from the group consisting of carbamoyl; R ¹⁴ is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, urea or carbamoyl ;
W is hydrogen, F, Cl, Br, I or OH;
X is hydrogen; and Y is OR ⁷ ; where R ⁷ is a monosaccharide or disaccharide containing hydrogen, amino sugar or halo sugar, alkyl, aryl, heteroaryl, eg 4-nitro-phenyl Acyl such as acetyl and 2-pyridylacetyl, or —C (O) NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are each independently hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, hetero Selected from alkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl, urea and carbamoyl; or X and Y together with the carbons to which they are attached form C = O ).

In one embodiment of the compounds of formula (I), V is C═O; X and Y together with the carbons to which they are attached form C═O. In another embodiment, R ¹ is a monosaccharide comprising an optionally protected 2′-hydroxy group. In another embodiment, R ¹ is a monosaccharide containing a protected 2′-hydroxy group, in which case the protecting group is a sterically hindered acyl group, eg, a branched alkylacyl group, an arylacyl group, a heteroaryl An acyl group, an arylalkylacyl group, an arylalkylacyl group or a heteroarylalkylacyl group, each of which is optionally substituted. In another embodiment, -A-B- is alkylene, cycloalkylene, or arylene; and C is optionally substituted aryl or heteroaryl. In another embodiment, R ¹ is desosamine; -AB- is 1,4-butylene and C is 4- (3-aminophenyl). In another embodiment, W is F. In another embodiment, R ¹ is desosamine containing a protected 2′-hydroxyl group, in which case the protecting group is a sterically hindered acyl group. In another embodiment, the sterically hindered acyl group is benzoyl or substituted benzoyl.

式中、Ｒ^１ａは立体障害アシル基であり、かつ、Ａ、Ｂ、ＣおよびＶは本明細書中に記載される通りである。式（ＩＩ）の化合物の１つの態様において、−Ａ−Ｂ−が、アルキレン、シクロアルキレンまたはアリーレンであり；かつ、Ｃが、任意に置換されたアリールまたはヘテロアリールである。別の態様において、Ｒ^１ａがベンゾイルであり；−Ａ−Ｂ−が、１，４−ブチレンであり、かつ、Ｃが、４−（３−アミノフェニル）である。 In another exemplary embodiment, a process for preparing a compound of formula (II) below is described:

In which R ^1a is a sterically hindered acyl group and A, B, C and V are as described herein. In one embodiment of the compounds of formula (II), -A-B- is alkylene, cycloalkylene or arylene; and C is optionally substituted aryl or heteroaryl. In another embodiment, R ^1a is benzoyl; -A-B- is 1,4-butylene and C is 4- (3-aminophenyl).

式中、Ａ、Ｂ、ＣおよびＶは、本明細書中に記載される通りである。式（ＩＩＩ）の化合物の１つの態様において、−Ａ−Ｂ−が、アルキレン、シクロアルキレンまたはアリーレンであり；かつ、Ｃが、任意に置換されたアリールまたはヘテロアリールである。別の態様において、−Ａ−Ｂ−が、１，４−ブチレンであり、かつ、Ｃが、４−（３−アミノフェニル）である。 In another exemplary embodiment, a process for preparing a compound of formula (III) below is described:

In which A, B, C and V are as described herein. In one embodiment of the compounds of formula (III), -AB- is alkylene, cycloalkylene or arylene; and C is optionally substituted aryl or heteroaryl. In another embodiment, -A-B- is 1,4-butylene and C is 4- (3-aminophenyl).

（式中、Ｒ^１は、２’−ヒドロキシル基を含む単糖類であり、かつ、Ｖ、Ｗ、ＸおよびＹは、本明細書中で定義される通りである）を、立体障害アシル化剤Ｒ^１ａ−Ｌ（式中、Ｒ^１ａは立体障害アシル基であり、かつ、Ｌは脱離基または活性化基である）と反応させることによって、対応する２’−アシル誘導体を形成する工程である。例示として、このプロセスは、下記のように、化合物（１）を立体障害アシル化剤と反応させることによって、対応する２’−アシル誘導体または２’，４’’−ジアシル誘導体、すなわち、化合物（２）を形成する、（ａ）工程を含む：

式中、ＷおよびＲ^１ａは本明細書中で定義される通りである。 In another exemplary embodiment, a process for preparing a compound of formula (I), formula (II) or formula (III) is described, comprising the following step (a). Here, the step (a) is a compound of the following formula (IV):

Wherein R ¹ is a monosaccharide containing a 2′-hydroxyl group, and V, W, X and Y are as defined herein. In the step of forming the corresponding 2′-acyl derivative by reacting with R ^1a -L (wherein R ^1a is a sterically hindered acyl group and L is a leaving group or an activating group). is there. Illustratively, this process can be accomplished by reacting compound (1) with a sterically hindered acylating agent as described below to produce the corresponding 2′-acyl derivative or 2 ′, 4 ″ -diacyl derivative, ie, compound ( 2), comprising the step (a):

In which W and R ^1a are as defined herein.

式中、Ｌは脱離基であり、かつ、Ｒ^１、Ｖ、Ｗ、ＸおよびＹは、本明細書中で定義される通りである。例示として、このプロセスは、化合物（２）をカルボニルジイミダゾールと反応させることによって、下記の化合物（３）を調製する、（ｂ）工程を含む：

式中、Ｒ^１ａおよびＷは、本明細書中で定義される通りである。 In another exemplary embodiment, a process for preparing a compound of formula (I), formula (II) or formula (III) is described, comprising the following step (b). Here, step (b) is a step of forming a compound of formula (V) by reacting a compound of formula (IV) with a carbonylating reagent:

Where L is a leaving group and R ¹ , V, W, X and Y are as defined herein. Illustratively, this process comprises the step (b), which prepares the following compound (3) by reacting compound (2) with carbonyldiimidazole:

In which R ^1a and W are as defined herein.

式中、Ｒ^１、Ａ、Ｂ、Ｖ、Ｗ、ＸおよびＹは、本明細書中で定義される通りである。１つの変形例において、ＡおよびＢは一緒になって、アルキレン、スピロシクロアルキレンを含むシクロアルキレン、またはアリーレン（これらのそれぞれが任意に置換される）を形成する。例示として、このプロセスは、化合物（３）を、Ｎ_３−Ｂ−Ａ−ＮＨ_２と反応させることによって、下記の化合物（４）を得る、（ｃ）工程を含む：

式中、Ｒ^１ａ、Ａ、ＢおよびＷは、本明細書中に記載される通りである。 In another exemplary embodiment, a process for preparing a compound of formula (I), formula (II) or formula (III) is described, comprising the following step (c). Here, the step (c) is a step of obtaining a compound of the following formula (VI) by reacting a compound of the formula (V) with a compound of the formula N ₃ —BA—NH ₂ :

Wherein R ¹ , A, B, V, W, X and Y are as defined herein. In one variation, A and B are taken together to form alkylene, cycloalkylene, including spirocycloalkylene, or arylene, each of which is optionally substituted. Illustratively, this process comprises the step (c), wherein compound (3) is reacted with N ₃ -BA-NH ₂ to give the following compound (4):

Wherein R ^1a , A, B and W are as described herein.

式中、Ｒ^１ａ、Ａ、ＢおよびＷは、本明細書中に記載される通りである。 In another exemplary embodiment, a process for preparing a compound of formula (I), formula (II) or formula (III) is described, comprising the following step (d): Here, in step (d), the compound of formula (I) (wherein X is hydrogen and Y is OR ⁷ ; in which R ⁷ is a monosaccharide or a disaccharide) This is a step for preparing a corresponding compound of formula (I) wherein R ⁷ is hydrogen by reacting with an acid. By way of example, this process comprises the step (d), wherein the following compound (5) is prepared by reacting compound (4) with an acid:

Wherein R ^1a , A, B and W are as described herein.

式中、Ｒ^１ａ、Ａ、ＢおよびＷは、本明細書中に記載される通りである。 In another exemplary embodiment, a process for preparing a compound of formula (I), formula (II) or formula (III) is described, comprising the following step (e): Here, the step (e) is carried out by oxidizing a compound of the formula (I) (wherein X is hydrogen and Y is OH) to oxidize the corresponding compound of the formula (I) (wherein , X and Y, together with the carbon to which they are attached, forms C = O). Illustratively, this process comprises the step (e) of preparing the following compound (6) by oxidizing compound (5) with an oxidizing agent:

Wherein R ^1a , A, B and W are as described herein.

式中、Ｒ^１ａ、ＡおよびＢは、本明細書中に記載される通りである。 In another exemplary embodiment, a process for preparing a compound of formula (I), formula (II) or formula (III) is described, comprising the following step (f). Here, in step (f), the compound of formula (I) (wherein W is hydrogen) is reacted with a fluorinating agent to react the corresponding compound of formula (I) (wherein W is F). Illustratively, this process comprises the step (f), which prepares the following compound (7) by reacting compound (6) with a fluorinating agent:

In which R ^1a , A and B are as described herein.

式中、Ｒ^４およびＲ^５はそれぞれが独立して、水素、アルキル、ヘテロアルキル、アリールおよびヘテロアリール（これらのそれぞれが任意に置換される）からなる群から選択され、かつ、Ｒ^１、Ａ、Ｂ、Ｖ、Ｗ、ＸおよびＹは本明細書中に記載される通りである。１つの態様において、Ｒ^４およびＲ^５はともに、水素ではない。別の態様において、Ｒ^４およびＲ^５の少なくとも１つが水素である。１つの変形例において、ＡおよびＢは一緒になって、アルキレン、スピロシクロアルキレンを含むシクロアルキレン、または、アリーレン（これらのそれぞれが任意に置換される）を形成する。例示として、このプロセスは、銅触媒および塩基の存在下で、Ｈｕｉｓｇｅｎ環化を化合物（７）に対して行うことによって、下記の化合物（８）を調製する、（ｇ）工程を含む：

式中、Ｒ^１ａ、ＡおよびＢは本明細書中に記載される通りである。 In another exemplary embodiment, the method comprises converting the azide group in the compound of formula (VI) to the corresponding compound of formula (I) having a 1,2,3-triazole group, Processes for preparing compounds of formula (II) or formula (III) are described. By way of example, a process for preparing a compound of formula (I), formula (II) or formula (III) is described, comprising the following step (g). Here, step (g) is a step of obtaining a compound of the following formula (VII) by reacting a compound of formula (VI) with R ⁴ , R ⁵ -substituted alkyne:

Wherein R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl, each of which is optionally substituted, and R ¹ , A , B, V, W, X and Y are as described herein. In one embodiment, R ⁴ and R ⁵ are not both hydrogen. In another embodiment, at least one of R ⁴ and R ⁵ is hydrogen. In one variation, A and B are taken together to form alkylene, cycloalkylene, including spirocycloalkylene, or arylene, each of which is optionally substituted. Illustratively, this process comprises the following step (g), wherein the following compound (8) is prepared by performing a Huisgen cyclization on compound (7) in the presence of a copper catalyst and a base:

Wherein R ^1a , A and B are as described herein.

式中、ＡおよびＢは、本明細書中で定義される通りである。 In another exemplary embodiment, a process for preparing a compound of formula (I) is described, comprising the following step (h). Here, step (h) comprises reacting a compound of formula (I) (wherein R ¹ is a monosaccharide or polysaccharide having an acyl protecting group) with an alcohol. Wherein the corresponding deprotected compound is prepared. In one variation, a process for preparing a compound of formula (III) is described that comprises reacting a compound of formula (II) with an alcohol. Illustratively, this process comprises the step (h), wherein the following compound (9) is prepared by reacting compound (8) with an alcohol:

In which A and B are as defined herein.

  It will be appreciated that the processes described herein may be advantageously performed conveniently and cost effectively. It is further understood that the processes described herein can be scaled up to large production batches. It is further understood that the processes described herein are performed with fewer steps than conventional processes. It is further understood that the processes described herein are performed with more intensive steps than conventional processes and with less linear steps than conventional processes. It is further understood that the processes described herein can be accompanied by fewer by-products or different by-products than known processes. It is further understood that the processes described herein can provide the compounds described herein in a higher purity than known processes.

In one exemplary embodiment, a process for preparing a compound of formula (I), formula (II) and formula (III), wherein R ¹ is a monosaccharide or polysaccharide is Are described herein. In one embodiment, the monosaccharide is an amino sugar or a derivative thereof, for example, micaminose derivatized at the C-4 ′ position, desosamine, 4-deoxy-3-amino derivatized at the C-6 ′ position. -Glucose, chloramphenicol, clindamycin, etc., or these analogs or derivatives. In another embodiment, the polysaccharide is, for example, micaminose derivatized at the C-4 ′ position with another sugar, or 4-deoxy-3-amino derivatized at the C-6 ′ position with another sugar. A disaccharide which is glucose, for example a trisaccharide which is an amino sugar or a halo sugar, or an analogue or derivative thereof. In another embodiment, R ¹ is desosamine or an analog or derivative thereof. It should be understood that in this and other embodiments, derivatives include protected forms of monosaccharides or polysaccharides.

（式中、Ｒ^１は、２’−ヒドロキシル基を含む単糖類であり、かつ、Ｖ、Ｗ、ＸおよびＹは、本明細書中で定義される通りである）を、立体障害アシル化剤Ｒ^１ａ−Ｌ（式中、Ｒ^１ａは立体障害アシル基であり、かつ、Ｌは脱離基または活性化基である）と反応させることによって、対応する２’−アシル誘導体を形成する工程である。Ｒ^１に存在するか、または、基Ｙに含まれるさらなるヒドロキシル基もまた、このプロセスではアシル化され得ることが理解される。 In another exemplary embodiment, a process for preparing a compound of formula (I), formula (II) or formula (III) is described, comprising the following step (a). Here, the step (a) is a compound of the following formula (IV):

Wherein R ¹ is a monosaccharide containing a 2′-hydroxyl group, and V, W, X and Y are as defined herein. In the step of forming the corresponding 2′-acyl derivative by reacting with R ^1a -L (wherein R ^1a is a sterically hindered acyl group and L is a leaving group or an activating group). is there. It is understood that additional hydroxyl groups present in R ¹ or included in the group Y can also be acylated in this process.

式中、ＷおよびＲ^１ａは、本明細書中で定義される通りである。式（ＩＶ）、式（１）および式（２）の化合物の別の態様において、ＷがＦである。（１）を（２）に変換する１つの態様において、Ｒ^１ａは、任意に置換されたベンゾイル基であり、かつ、工程（ａ）は、安息香酸無水物、あるいは、式（ＩＶ）の化合物または代替的には化合物（１）の、２’位、または、２’位および４’位の両方においてベンゾイルエステルを形成することができる同等に活性化されたベンゾイル試薬を含む。 Exemplary sterically hindered acyl derivatives or sterically hindered diacyl derivatives include, but are not limited to, cyclohexylcarbonyl, benzoyl, pivaloyl, and the like. A wide variety of activating groups to form acyl derivatives can be used to prepare the required acylating agents, such as anhydrides, chlorides, triflates and bromides. But are not limited to these. In one embodiment, the sterically hindered acylating agent is a benzoic anhydride, or alternatively the 2′-position, or 2′-position and 4′-position of the compound of formula (IV) or alternatively compound (1) An equally activated benzoyl reagent capable of forming a benzoyl ester in both positions. Illustratively, this process forms the corresponding 2′-acyl derivative or 2 ′, 4 ″ -diacyl derivative, ie, compound (2), by reacting compound (1) with a sterically hindered acylating agent. Including the following step (a):

In which W and R ^1a are as defined herein. In another embodiment of the compounds of formula (IV), formula (1) and formula (2), W is F. In one embodiment of converting (1) to (2), R ^1a is an optionally substituted benzoyl group, and step (a) is benzoic anhydride or a compound of formula (IV) Or alternatively, an equivalent activated benzoyl reagent capable of forming a benzoyl ester at the 2 ′ position or both the 2 ′ and 4 ′ positions of compound (1).

  Step (a) is generally performed in the presence of a solvent and a base. Illustratively, the solvent includes, but is not limited to, ethyl acetate, dichloromethane, acetone and pyridine, and mixtures thereof. Exemplary bases include inorganic bases such as sodium and potassium bicarbonate, sodium and potassium carbonate, sodium hydroxide and potassium hydroxide, and mixtures thereof; and also amine bases such as pyridine , Dimethylaminopyridine (DMAP), triethylamine (TEA), diisopropylethylamine (DIPEA, Hunig base) and 1,4-diazabicyclo [2.2.2] octane (DABCO) and the like, and mixtures thereof, It is not limited to these. This reaction can be performed at various temperatures, for example, in the range of about 0 ° C. to about 60 ° C., and illustratively can be performed at about 10 ° C. to about 30 ° C.

式中、Ｌは脱離基であり、かつ、Ｒ^１、Ｖ、Ｗ、ＸおよびＹは、本明細書中で定義される通りである。工程（ｂ）は一般には、極性溶媒および塩基の存在下で行うことによって、式（Ｖ）の化合物を得る。例示的なカルボニル化剤には、クロロギ酸メチル、クロロギ酸ベンジルおよびクロロギ酸フェニル、カルボニルジイミダゾール、ホスゲン、ジホスゲン、トリホスゲン、１，１’−カルボニルビス（２−メチルイミダゾール）、［［１，１’−カルボニルジピペリジン，ビス（ペンタメチレン）ウレア］］、ジメチルカルボナート、ジエチルカルボナートおよびジプロピルカルボナートなどが含まれる。例示的な極性溶媒には、ジメチルホルムアミド（ＤＭＦ）、アセトニトリル、ＴＨＦおよびメチルテトラヒドロフランなど、ならびに、それらの混合物が含まれるが、これらに限定されない。例示的な塩基には、ＤＢＵ、ＤＡＢＣＯ、ＴＥＡおよびＤＩＰＥＡなど、ならびに、それらの混合物などが含まれるが、これらに限定されない。この反応は様々な温度で行うことができ、例えば、約０℃〜約６０℃の範囲において行うことができ、例示的には室温で行うことができる。例示として、このプロセスは、化合物（２）をカルボニルジイミダゾールと反応させることによって、下記の化合物（３）を調製する、（ｂ）工程を含む：

式中、Ｒ^１ａおよびＷは、本明細書中で定義される通りである。別の例示的な例において、このプロセスは、化合物（２）を、ＤＢＵの存在下でカルボニルジイミダゾールと反応させることによって、化合物（３）を調製する工程を含む。式（Ｖ）および式（３）の化合物の別の態様において、ＷがＦである。１つの変形例において、化合物（ＩＶ）が、最初にＭｓ_２Ｏ／ピリジンで処理され、その後にＤＢＵ／アセトン、その後にＮａＨ／ＣＤＩ／ＤＭＦと−１０℃で処理されることによって、化合物（Ｖ）が調製される。 In another exemplary embodiment, a process for preparing a compound of formula (I), formula (II) or formula (III) is described, comprising the following step (b). Here, step (b) is a step of forming a compound of formula (V) by reacting a compound of formula (IV) with a carbonylating reagent:

Where L is a leaving group and R ¹ , V, W, X and Y are as defined herein. Step (b) is generally performed in the presence of a polar solvent and a base to obtain a compound of formula (V). Exemplary carbonylating agents include methyl chloroformate, benzyl chloroformate and phenyl chloroformate, carbonyldiimidazole, phosgene, diphosgene, triphosgene, 1,1′-carbonylbis (2-methylimidazole), [[1,1 '-Carbonyldipiperidine, bis (pentamethylene) urea]], dimethyl carbonate, diethyl carbonate, dipropyl carbonate and the like. Exemplary polar solvents include, but are not limited to, dimethylformamide (DMF), acetonitrile, THF and methyltetrahydrofuran, and mixtures thereof. Exemplary bases include, but are not limited to, DBU, DABCO, TEA and DIPEA, and mixtures thereof. This reaction can be performed at various temperatures, for example, in the range of about 0 ° C. to about 60 ° C., illustratively at room temperature. Illustratively, this process comprises the step (b), which prepares the following compound (3) by reacting compound (2) with carbonyldiimidazole:

In which R ^1a and W are as defined herein. In another illustrative example, the process includes preparing compound (3) by reacting compound (2) with carbonyldiimidazole in the presence of DBU. In another embodiment of the compounds of formula (V) and formula (3), W is F. In one variation, compound (IV) is first treated with Ms ₂ O / pyridine, followed by treatment with DBU / acetone followed by NaH / CDI / DMF at −10 ° C. to give compound (V ) Is prepared.

式中、Ｒ^１、Ａ、Ｂ、Ｖ、Ｗ、ＸおよびＹは、本明細書中に記載される通りである。１つの変形例において、ＡおよびＢは一緒になって、アルキレン、スピロシクロアルキレンを含むシクロアルキレンまたはアリーレン（これらのそれぞれが任意に置換される）を形成する。−Ａ−Ｂ−の例示的な基には、１，４−ブチレン、１，４−ペンチレン、１，５−ペンチレン、１，１−シクロプロピリデン、１，１−シクロペンチリデンおよび１−シクロプロパ−１−イルプロピルなどが含まれるが、これらに限定されない。１つの態様において、−Ａ−Ｂ−は、直線状のＣ_２〜Ｃ_１０アルキレンである。別の態様において、−Ａ−Ｂ−は、直線状のＣ_３〜Ｃ_５アルキレンである。別の態様において、−Ａ−Ｂ−は、１，４−ブチレンである。 In another exemplary embodiment, a process for preparing a compound of formula (I), formula (II) or formula (III) is described, comprising the following step (c). Here, the step (c) is a step of obtaining a compound of the following formula (VI) by reacting a compound of the formula (V) with a compound of the formula N ₃ —BA—NH ₂ :

In which R ¹ , A, B, V, W, X and Y are as described herein. In one variation, A and B are taken together to form alkylene, cycloalkylene, including spirocycloalkylene, or arylene, each of which is optionally substituted. Exemplary groups of -A-B- include 1,4-butylene, 1,4-pentylene, 1,5-pentylene, 1,1-cyclopropylidene, 1,1-cyclopentylidene and 1-cyclopropylene. Including, but not limited to, -1-ylpropyl and the like. In one embodiment, -A-B- is a linear _C 2 _{-C 10} alkylene. In another embodiment, -A-B- is a linear _C 3 -C ₅ alkylene. In another embodiment, -A-B- is 1,4-butylene.

  Step (c) is generally performed in the presence of a polar solvent, including protic polar solvents and aprotic polar solvents, or mixtures thereof. Exemplary protic polar solvents include water, alcohols (eg, methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butyl alcohol, tert-butyl alcohol, methoxyethanol, ethoxyethanol, pentanol, neo -Pentyl alcohol, tert-pentyl alcohol, cyclohexanol, ethylene glycol, propylene glycol, and benzyl alcohol), formamide, N-methylacetamide, N-methylformamide, glycerol, and the like, and mixtures thereof. It is not limited to. Exemplary aprotic polar solvents include dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU), 1 , 3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, HMPA, HMPT, acetone, ethyl methyl ketone, Including ethyl acetate, isopropyl acetate, t-butyl acetate, sulfolane, N, N-dimethylpropionamide, nitromethane, nitrobenzene, tetrahydrofuran (THF), methyltetrahydrofuran, dioxane and polyethers, and mixtures thereof But it is not limited to these. In addition, step (c) can be performed in the presence of an additional base. Exemplary bases include, but are not limited to, DBU, DABCO, TEA and DIPEA, and mixtures thereof.

式中、Ｒ^１ａ、Ａ、ＢおよびＷは、本明細書中に記載される通りである。１つの例示的な実施形態において、Ｎ_３−Ｂ−Ａ−ＮＨ_２対化合物（３）のモル当量比が、約４対１から約３対１までである。別の例示的な実施形態において、Ｎ_３−Ｂ−Ａ−ＮＨ_２対化合物（３）のモル当量比が、約３対１である。別の例示的な実施形態において、Ｎ_３−Ｂ−Ａ−ＮＨ_２対化合物（３）のモル当量比が、約３対１であり、かつ、さらなる塩基が、ＤＢＵであり、ＤＢＵ対化合物（３）のモル当量比は、約１対１から約０．７５対１までである。別の例示的な実施形態において、Ｎ_３−Ｂ−Ａ−ＮＨ_２対化合物（３）のモル当量比が、約３対１であり、かつ、さらなる塩基が、ＤＢＵであり、ＤＢＵ対化合物（３）のモル当量比は、約０．７５対１である。 Illustratively, this process comprises the step (c), wherein compound (3) is reacted with N ₃ -BA-NH ₂ to give the following compound (4):

Wherein R ^1a , A, B and W are as described herein. In one exemplary _embodiment, the molar equivalent ratio of N 3 -B-A-NH ₂ to compound (3) is from about 4: 1 to about 3: 1. In another exemplary _embodiment, the molar equivalent ratio of N 3 -B-A-NH ₂ to compound (3) is from about 3: 1. In another exemplary _embodiment, the molar equivalent ratio of N 3 -B-A-NH ₂ to compound (3) is from about 3: 1, and additional base is a DBU, DBU to compound ( The molar equivalent ratio of 3) is from about 1 to 1 to about 0.75 to 1. In another exemplary _embodiment, the molar equivalent ratio of N 3 -B-A-NH ₂ to compound (3) is from about 3: 1, and additional base is a DBU, DBU to compound ( The molar equivalent ratio of 3) is about 0.75 to 1.

In another exemplary embodiment, a process for preparing a compound of formula (I), formula (II) or formula (III) is described, comprising the following step (d): Here, in step (d), the compound of formula (I) (wherein X is hydrogen and Y is OR ⁷ ; in which R ⁷ is a monosaccharide or a disaccharide) This is a step for preparing a corresponding compound of formula (I) wherein R ⁷ is hydrogen by reacting with an acid. Exemplary acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, trifluoroacetic acid, formic acid and hydrofluoric acid, and mixtures thereof. Not. In one variation, the acid is hydrochloric acid. Step (d) is generally performed in a solvent, such as water, polar organic solvents (including, for example, alcohols such as methanol, ethanol, isopropanol, n-propanol, tert-butanol and n-butanol), and It is carried out in a mixture thereof. Step (d) can be performed at a wide variety of temperatures, including temperatures ranging from about 0 ° C. to about 70 ° C., illustratively at temperatures ranging from about 20 ° C. to about 60 ° C. be able to.

式中、Ｒ^１ａ、Ａ、ＢおよびＷは、本明細書中に記載される通りである。式（ＶＩ）、式（４）および式（５）の化合物の１つの態様において、ＷがＦである。工程（ｄ）において使用される例示的な酸には、トリフルオロ酢酸、ギ酸、塩酸、臭化水素酸、硫酸、硝酸、リン酸、過塩素酸およびフッ化水素酸など、ならびに、それらの混合物が含まれるが、これらに限定されない。 By way of example, this process comprises the step (d), wherein the following compound (5) is prepared by reacting compound (4) with an acid:

Wherein R ^1a , A, B and W are as described herein. In one embodiment of the compounds of formula (VI), formula (4) and formula (5), W is F. Exemplary acids used in step (d) include trifluoroacetic acid, formic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid and hydrofluoric acid, and mixtures thereof. Is included, but is not limited thereto.

In another exemplary embodiment, a process for preparing a compound of formula (I), formula (II) or formula (III) is described, comprising the following step (e): Here, the step (e) is carried out by oxidizing a compound of the formula (I) (wherein X is hydrogen and Y is OH) to oxidize the corresponding compound of the formula (I) (wherein , X and Y, together with the carbon to which they are attached, forms C = O). Step (e) generally involves Corey-Kim oxidation (eg, dimethyl sulfide / N-chlorosuccinimide (DMS / NCS) and di-n-butyl sulfide / N-chlorosuccinimide), Dess-Martin reagent, Pfitzner- Moffat method and modifications thereof, Swern conditions (eg DMSO / oxalyl chloride, DMSO / phosphorus pentoxide, DMSO / p-toluenesulfonyl chloride, DMSO / acetic anhydride, DMSO / trifluoroacetic anhydride, and DMSO / thionyl chloride) ), Manganese reagent, chromium reagent, selenium reagent, tertiary amine oxide, Ni (Ac) ₂ / hypochlorite, and DMSO / EDAC · HCl / pyridine · TFA, and also, for example, one or Multiple phase transfer catalysts Including variants thereof due Mukoto it is carried out using a conventional oxidizing agent and conditions, without limitation.

式中、Ｒ^１ａ、Ａ、ＢおよびＷは、本明細書中に記載される通りである。式（６）の化合物の１つの態様において、ＷがＦである。１つの例示的な態様において、酸化剤が、Ｓｗｅｒｎ条件（例えば、ＤＭＳＯ／ＥＤＡＣ・ＨＣｌ／ピリジン・ＴＦＡ）、Ｄｅｓｓ−Ｍａｒｔｉｎ条件、Ｃｏｒｅｙ−Ｋｉｍ条件（例えば、ジメチルスルフィド／Ｎ−クロロスクシンイミド）、Ｊｏｎｅｓ試薬および他のクロム系酸化剤、過マンガン酸塩および他のマンガン系酸化剤、ならびに、Ｎｉ（Ａｃ）_２／次亜塩素酸塩などからなる群から選択される。例示的には、酸化が、ジメチルスルフィド、Ｎ−クロロスクシンイミドおよびトリエチルアミンを使用して、塩化メチレン中、約−２０℃〜０℃の温度で行われる。別の例示的な実施形態において、酸化が、Ｄｅｓｓ−Ｍａｒｔｉｎペルヨージナンを使用して、塩化メチレン中、約５℃〜約３０℃の温度で行われる。別の例示的な実施形態において、酸化が、Ｄｅｓｓ−Ｍａｒｔｉｎペルヨージナンを使用して、塩化メチレン中、約５℃〜約３０℃の温度で行われ、かつ、Ｄｅｓｓ−Ｍａｒｔｉｎペルヨージナン対化合物（５）のモル当量比が、約３．３対１から約１．３対１までである。別の例示的な実施形態において、酸化が、Ｄｅｓｓ−Ｍａｒｔｉｎペルヨージナンを使用して、塩化メチレン中、約５℃〜約３０℃の温度で行われ、かつ、Ｄｅｓｓ−Ｍａｒｔｉｎペルヨージナン対化合物（５）のモル当量比が、約１．３対１である。 Illustratively, this process comprises the step (e) of preparing the following compound (6) by oxidizing compound (5) with an oxidizing agent:

Wherein R ^1a , A, B and W are as described herein. In one embodiment of the compounds of formula (6), W is F. In one exemplary embodiment, the oxidizing agent may be a Swern condition (eg, DMSO / EDAC.HCl / pyridine / TFA), a Dess-Martin condition, a Corey-Kim condition (eg, dimethyl sulfide / N-chlorosuccinimide), Jones. Selected from the group consisting of reagents and other chromium-based oxidants, permanganate and other manganese-based oxidants, and Ni (Ac) ₂ / hypochlorite. Illustratively, the oxidation is performed in methylene chloride at a temperature of about −20 ° C. to 0 ° C. using dimethyl sulfide, N-chlorosuccinimide and triethylamine. In another exemplary embodiment, the oxidation is performed in methylene chloride at a temperature of about 5 ° C. to about 30 ° C. using Dess-Martin periodinane. In another exemplary embodiment, the oxidation is performed in a methylene chloride at a temperature of about 5 ° C. to about 30 ° C. using Dess-Martin periodinane and the Dess-Martin periodinane versus compound (5) The molar equivalent ratio is from about 3.3 to 1 to about 1.3 to 1. In another exemplary embodiment, the oxidation is performed in a methylene chloride at a temperature of about 5 ° C. to about 30 ° C. using Dess-Martin periodinane and the Dess-Martin periodinane versus compound (5) The molar equivalent ratio is about 1.3 to 1.

式中、Ｒ^１ａ、ＡおよびＢは、本明細書中に記載される通りである。フッ素化剤および塩基の他の組合せによっても、化合物（７）が調製され得ることが理解される。このフッ素化反応は一般には、例えば、水素化ナトリウム、炭酸ナトリウムまたはカリウム、および、重炭酸ナトリウムまたはカリウムなどである無機塩基；例えば、トリエチルアミン、ＤＡＢＣＯおよびカリウムｔｅｒｔ−ブトキシドなどである有機塩基；または、それらの組合せの存在下において行われる。このフッ素化反応は一般には、テトラヒドロフランおよびメチルテトラヒドロフランなど、または、それらの混合物を含めて、溶媒の存在下で行われるが、これらに限定されない。１つの例示的な実施形態において、フッ素化剤がＮ−フルオロスルホンイミドであり、塩基がカリウムｔｅｒｔ−ブトキシドであり、かつ、溶媒がテトラヒドロフランである。別の例示的な実施形態において、Ｎ−フルオロスルホンイミド対化合物（６）のモル当量比が、約１．３対１から約１．２対１までである。 In another exemplary embodiment, a process for preparing a compound of formula (I), formula (II) or formula (III) is described, comprising the following step (f). Here, in step (f), the compound of formula (I) (wherein W is hydrogen) is reacted with a fluorinating agent to react the corresponding compound of formula (I) (wherein W is F). Illustratively, this process involves compound (6) in the presence of a solvent and a base such as t-BuOK, for example (PhSO ₂ ) ₂ NF (NFSI or N-fluorosulfonimide), F-TEDA, By reacting with a fluorinating agent such as F-TEDA-BF ₄ and 1-fluoro-4-hydroxy-1,4-diazoniabicyclo [2.2.2] octanebis (tetrafluoroborate), the following Comprising step (f) of preparing compound (7):

In which R ^1a , A and B are as described herein. It is understood that compound (7) can also be prepared by other combinations of fluorinating agents and bases. This fluorination reaction is generally performed by, for example, an inorganic base such as sodium hydride, sodium or potassium carbonate, and sodium or potassium bicarbonate; an organic base such as triethylamine, DABCO, and potassium tert-butoxide; or It is carried out in the presence of those combinations. This fluorination reaction is generally performed in the presence of a solvent, including but not limited to tetrahydrofuran, methyltetrahydrofuran, and the like, or mixtures thereof. In one exemplary embodiment, the fluorinating agent is N-fluorosulfonimide, the base is potassium tert-butoxide, and the solvent is tetrahydrofuran. In another exemplary embodiment, the molar equivalent ratio of N-fluorosulfonimide to compound (6) is from about 1.3 to 1 to about 1.2 to 1.

式中、Ｒ^４およびＲ^５はそれぞれが独立して、水素、アルキル、ヘテロアルキル、アリールおよびヘテロアリール（これらのそれぞれが任意に置換される）からなる群から選択され、かつ、Ｒ^１、Ａ、Ｂ、Ｖ、Ｗ、ＸおよびＹは、本明細書中に記載される通りである。１つの態様において、Ｒ^４およびＲ^５はともに、水素ではない。別の態様において、Ｒ^４およびＲ^５の少なくとも１つが水素である。式（ＶＩＩ）の化合物の別の態様において、ＷがＦである。１つの変形例において、ＡおよびＢは一緒になって、アルキレン、スピロシクロアルキレンを含むシクロアルキレンまたはアリーレン（これらのそれぞれが任意に置換される）を形成する。例示的な置換されたアルキンには、芳香族基、置換された芳香族基、複素環式基、置換された複素環式基、アルキル基、分岐したアルキル基、置換されたアルキル基（例えば、第一級アミノ基、第二級アミノ基および第三級アミノ基を含むアミノ基により置換されるアルキル基など）、１つまたは複数のハロゲン、ヒドロキシル、アルキルエーテルおよび芳香族エーテルを含むエーテル、ケトン、チオエーテル、エステル、カルボン酸、シアノおよびエポキシドなどにより置換される、アルキンが含まれる。 In another exemplary embodiment, the method comprises converting the azide group in the compound of formula (VI) to the corresponding compound of formula (I) having a 1,2,3-triazole group, Processes for preparing compounds of formula (II) or formula (III) are described. By way of example, a process for preparing a compound of formula (I), formula (II) or formula (III) is described, comprising the following step (g). Here, step (g) is a step of obtaining a compound of the following formula (VII) by reacting a compound of formula (VI) with R ⁴ , R ⁵ -substituted alkyne:

Wherein R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl, each of which is optionally substituted, and R ¹ , A , B, V, W, X and Y are as described herein. In one embodiment, R ⁴ and R ⁵ are not both hydrogen. In another embodiment, at least one of R ⁴ and R ⁵ is hydrogen. In another embodiment of the compounds of formula (VII), W is F. In one variation, A and B are taken together to form alkylene, cycloalkylene, including spirocycloalkylene, or arylene, each of which is optionally substituted. Exemplary substituted alkynes include aromatic groups, substituted aromatic groups, heterocyclic groups, substituted heterocyclic groups, alkyl groups, branched alkyl groups, substituted alkyl groups (e.g., Ethers, ketones including one or more halogens, hydroxyls, alkyl ethers and aromatic ethers, such as alkyl groups substituted by amino groups including primary amino groups, secondary amino groups and tertiary amino groups) Alkynes substituted by thioethers, esters, carboxylic acids, cyano, epoxides, and the like.

式中、Ｒ^１ａ、ＡおよびＢは、本明細書中に記載される通りである。工程（ｇ）におけるＨｕｉｓｇｅｎ環化は、塩基の存在下で、無溶媒、水中、または、例えばアセトニトリルまたはトルエンである有機溶媒中のいずれかにおいて行われる。例示的な塩基には、例えば、トリエチルアミン、ジイソプロピルエチルアミン、ＤＡＢＣＯ、ピリジンおよびルチジンなどの、アルキル塩基およびヘテロアリール塩基を含む有機塩基、ならびに、例えば、ＮａＯＨ、ＫＯＨ、Ｋ_２ＣＯ_３およびＮａＨＣＯ_３などの無機塩基が含まれるが、これらに限定されない。塩基は例示的には、ジイソプロピルエチルアミン（ＤＩＰＥＡ）である。１つの実施形態において、３−アミノフェニルエチン対化合物（７）の比率が、約１．５対１から約１．２対１までであり、かつ、ＤＩＰＥＡ対化合物（７）の比率が、約１０対１から約４対１までである。反応は、２０℃から８０℃までの温度で行われる。この反応はまた、触媒の使用により促進させることができ、そのような触媒には、例示的にはヨウ化銅であるハロゲン化銅が含まれるが、これらに限定されない。ＣｕＩの、アジド（ＶＩ）または（７）に対する比率が、例示的には、約０．０１対１から約０．１対１である。１つの例示的な実施例において、ＣｕＩの、アジド（ＶＩ）または（７）に対する比率が、０．０３対１である。代替的な実施形態において、触媒は、例えばフェノールフタレインである有機触媒である。さらなる反応条件が、Ｓｈａｒｐｌｅｓｓらによって米国特許出願公開第２００５／０２２２４２７号に、Ｌｉａｎｇらによって、Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．、１５（２００５）、１３０７〜１３１０に、また、Ｒｏｍｅｒｏらによって、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔｅｒｓ、４６（２００５）、１４８３〜１４８７に記載される（これらの開示は参照によって本明細書中に組み込まれる）。 Illustratively, this process comprises the following step (g), which prepares the following compound (8) by performing a Huisgen cyclization on compound (7) in the presence of a copper catalyst and a base:

In which R ^1a , A and B are as described herein. The Huisgen cyclization in step (g) is performed either in the absence of a base, in water, or in an organic solvent such as acetonitrile or toluene. Exemplary bases include, for example, organic bases including alkyl bases and heteroaryl bases such as triethylamine, diisopropylethylamine, DABCO, pyridine and lutidine, as well as, for example, NaOH, KOH, K ₂ CO ₃ and NaHCO ₃ . Inorganic bases are included, but are not limited to these. The base is illustratively diisopropylethylamine (DIPEA). In one embodiment, the ratio of 3-aminophenylethyne to compound (7) is from about 1.5 to 1 to about 1.2 to 1, and the ratio of DIPEA to compound (7) is about 10: 1 to about 4: 1. The reaction is carried out at a temperature from 20 ° C to 80 ° C. This reaction can also be facilitated by the use of catalysts, such catalysts include but are not limited to copper halide, illustratively copper iodide. The ratio of CuI to azide (VI) or (7) is illustratively from about 0.01 to 1 to about 0.1 to 1. In one exemplary embodiment, the ratio of CuI to azide (VI) or (7) is 0.03 to 1. In an alternative embodiment, the catalyst is an organic catalyst, for example phenolphthalein. Additional reaction conditions are described by Sharpless et al. In US Patent Application Publication No. 2005/0222427, Liang et al., Bioorg. Med. Chem. Lett. 15 (2005), 1307-1310, and by Romero et al., Tetrahedron Letters, 46 (2005), 1483-1487, the disclosures of which are incorporated herein by reference.

式中、ＡおよびＢは、本明細書中で定義される通りである。工程（ｈ）において使用されるアルコールは、メタノール、エタノール、ｎ−プロパノール、イソプロパノール、ｔｅｒｔ−ブタノール、ｎ−ブタノールまたはそれらの混合物から選択することができる。例示的には、アルコールはメタノールである。反応は、約０℃〜約１００℃の温度で行われ、好ましくは、約２０℃〜約７０℃で行われる。この反応はまた、ＨＣｌおよびＨ_２ＳＯ_４など、ならびに、それらの混合物からなる群から選択される、鉱酸の存在下で行うことができる。１つの例示的な実施形態において、反応が、メタノール中、約５５℃の温度で行われる。 In another exemplary embodiment, a process for preparing a compound of formula (I) is described, comprising the following step (h). Here, the step (h) comprises reacting a compound of formula (I) (wherein R ¹ is a monosaccharide or polysaccharide having an acyl protecting group) with an alcohol. A step of preparing the corresponding deprotected compound. In one variation, a process for preparing a compound of formula (III) is described that comprises reacting a compound of formula (II) with an alcohol. Illustratively, this process comprises the step (h), wherein the following compound (9) is prepared by reacting compound (8) with an alcohol:

In which A and B are as defined herein. The alcohol used in step (h) can be selected from methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol or mixtures thereof. Illustratively, the alcohol is methanol. The reaction is carried out at a temperature of about 0 ° C. to about 100 ° C., preferably at about 20 ° C. to about 70 ° C. This reaction can also be carried out in the presence of a mineral acid selected from the group consisting of HCl and H ₂ SO ₄ , and mixtures thereof. In one exemplary embodiment, the reaction is performed in methanol at a temperature of about 55 ° C.

  It should be understood that the steps described above for these various processes may generally be performed in a different order.

式中、Ｒ^１は、立体障害アシル化剤Ｒ^１ａ−Ｌ（式中、Ｒ^１ａは立体障害アシル基であり、かつ、Ｌは脱離基または活性化基である）によりアシル化される２’−ヒドロキシル基を含む、単糖類であり；かつ、Ｒ^４、Ｒ^５、Ａ、Ｂ、Ｖ、Ｗ、ＸおよびＹは、本明細書中で定義される通りである。工程（ｂ）、工程（ｃ）および工程（ｇ）は、本明細書中に記載されるように行われる。 In another embodiment, a process for preparing compounds of formula (I), formula (II) and formula (III) is described herein, wherein the process comprises the following steps:

Wherein R ¹ is acylated by a sterically hindered acylating agent R ^1a -L, wherein R ^1a is a sterically hindered acyl group and L is a leaving or activating group 2 A monosaccharide containing a '-hydroxyl group; and R ⁴ , R ⁵ , A, B, V, W, X and Y are as defined herein. Step (b), step (c) and step (g) are performed as described herein.

式中、Ｒ^１は、立体障害アシル化剤Ｒ^１ａ−Ｌ（式中、Ｒ^１ａは立体障害アシル基であり、かつ、Ｌは脱離基または活性化基である）によりアシル化される２’−ヒドロキシル基を含む、単糖類であり；かつ、Ａ、ＢおよびＷは、本明細書中で定義される通りである。工程（ａ）、工程（ｂ）、工程（ｃ）、工程（ｄ）、工程（ｅ）、工程（ｆ）、工程（ｇ）および工程（ｈ）は、本明細書中に記載されるように行われる。 In another embodiment, a process for preparing compounds of formula (I), formula (II) and formula (III) is described herein, wherein the process comprises the following steps:

Wherein R ¹ is acylated by a sterically hindered acylating agent R ^1a -L, wherein R ^1a is a sterically hindered acyl group and L is a leaving or activating group 2 A monosaccharide containing a '-hydroxyl group; and A, B and W are as defined herein. Step (a), Step (b), Step (c), Step (d), Step (e), Step (f), Step (g) and Step (h) are as described herein. To be done.

  In another embodiment, intermediates useful for preparing compounds of formula (I), formula (II) and formula (III) are described herein. Such intermediates include compound (1), compound (2), compound (3), compound (4), compound (5), compound (6), compound (7), compound (8) and compound ( 9) as well as compounds of formula (IV), formula (V), formula (VI) and formula (VII). It will be appreciated that such compounds are themselves useful in treating diseases, eg, bacterial infections. It will be appreciated that such compounds may also be useful in the preparation of antibiotic, antibacterial, anti-infective and / or antiviral compositions.

  In another embodiment, the processes described herein prepare compounds of formula (I), formula (II) and formula (III) in higher yield and / or purity than conventional processes. Useful for. In one embodiment, the process described herein can include pre-activation of a side chain hydroxyl group, for example by using tosyl chloride or an equivalent activating group, and subsequent corresponding side chain azide. Allows direct introduction of azide side chains into macrolide compounds without the need for conversion to groups. The direct introduction of the azide side chain as described herein is the total number of synthetic steps that must be performed in preparing the compounds of formula (I), formula (II) and formula (III). Reduce. Conventional synthesis discloses the introduction of side chains containing alcohol groups that must be converted to azides in a linear order over at least two steps.

In another aspect, the processes described herein reduce the number of side product reactions occurring, correspondingly during the preparation of compounds of formula (I), formula (II) and formula (III). Can reduce the number of unwanted impurities. The process described herein functions to protect the hydroxyl group in the sugar moiety of the macrolide, and other sugars in the compounds of formula (I), formula (II) and formula (III) It includes the use of sterically hindered acyl groups that also function to reduce the possibility of acyl transfer to the functional group. For example, it has been discovered that non-sterically hindered acyl groups present in C-5 sugars, for example acetyl groups, can be transferred to other positions in the macrolide compound. Specifically, in the case of compound (7), it has been discovered that when R ^1a is acetyl, the acetyl protecting group is transferred from desosamine to the side chain aniline amino group, resulting in unwanted products. And subsequent further purification steps. As described herein, the use of sterically hindered acyl protecting groups solves the problem of acyl transfer reactions during Huisgen cyclization. It is understood that avoiding acyl transfer can result in both improved yield as well as improved purity. Thus, the compounds of formula (I), and in particular compounds (8) and (9), can be obtained by precipitation, filtration, centrifugation, decantation and similar processes without the need for chromatographic purification methods. It has been discovered that it can be isolated. It will be appreciated that compounds of formula (I), and in particular compound (9), can be further purified by solid-liquid adsorption chromatography. In one exemplary embodiment, the solid adsorbent is selected from reverse phase adsorbent, silica gel, alumina or magnesia-silica gel and the like, and the developing solvent is ethyl acetate, isopropyl acetate, methylene chloride, heptane, cyclohexane. , Toluene, acetonitrile, methanol, isopropanol, ethanol, THF, water, etc., or combinations thereof. In another exemplary embodiment, the solid adsorbent is magnesia-silica gel.

In another aspect, the process described herein improves the purity of the compounds of formula (I), formula (II) and formula (III) described herein and / or Improves the purification of the compounds described herein. In the process described herein, a sterically hindered acyl group that functions to protect the hydroxyl group in the sugar moiety of the macrolide and also to provide more effective purification of the compound. Includes use. For example, it has been discovered that performing a Huisgen cyclization results in a mixture of a triazole compound of formula (VII) and an unreacted ethyne compound. When the triazole compound of formula (VII) contains a monosaccharide at unprotected R ¹ as described herein, these two compounds are difficult to separate. In contrast, when the triazole compound of formula (VII) contains a 2′-acyl protected monosaccharide at R ¹ , the triazole compound of formula (VII) is unexpectedly more easily separated from the unreacted ethyne compound. Is done. Thus, compounds of formula (VII), and in particular compounds (8) and (9), can be obtained by precipitation, filtration, centrifugation, decantation and similar processes without the need for chromatographic purification methods. It has been discovered that it can be isolated. It will be appreciated that compounds of formula (I), and in particular compound (9), can be further purified by solid-liquid chromatography. In one exemplary embodiment, the solid adsorbent is selected from reverse phase adsorbents, silica gel, alumina, magnesia-silica gel and the like, and the developing solvent is ethyl acetate, isopropyl acetate, methylene chloride, heptane, cyclohexane. , Toluene, acetonitrile, methanol, isopropanol, ethanol, THF, water, etc., or combinations thereof. In another exemplary embodiment, the solid adsorbent is magnesia-silica gel.

  In another embodiment, the compounds of formula (I), formula (II), and formula (III) have a purity greater than about 98%, a purity greater than about 99%, and a purity greater than about 99.5%. As described herein. In another embodiment, the compounds of formula (I), formula (II) and formula (III) comprise less than about 1% aminophenylethyne compound, less than about 0.5% aminophenylethyne compound, about 0.2% Described herein as containing less than% aminophenylethyne compounds and less than about 0.1% aminophenylethyne compounds. In another embodiment, the compounds of formula (I), formula (II) and formula (III) are as defined herein as substantially free of aminophenylethyne compounds or as free of aminophenylethyne compounds. Described in. In another embodiment, a composition comprising a compound of formula (I), formula (II) and formula (III) is compared to a compound of formula (I), formula (II) and formula (III) in the composition Less than about 1% aminophenylethyne compound, less than about 0.5% aminophenylethyne compound, less than about 0.15% aminophenylethyne compound, and less than about 0.1% aminophenylethyne compound As described herein. In another embodiment, the composition comprising compounds of formula (I), formula (II) and formula (III) is substantially free of aminophenylethyne compounds or as free of aminophenylethyne compounds. Are described herein.

  The term “aryl” refers to an optionally substituted aromatic ring system, whether alone or in combination. The term aryl includes monocyclic aromatic rings and polycyclic aromatic rings. Examples of aryl groups include, but are not limited to, phenyl ring systems, biphenyl ring systems, naphthyl ring systems, and anthryl ring systems.

  The term “heteroaryl” refers to an optionally substituted aromatic ring system having one or more heteroatoms, for example oxygen, nitrogen, sulfur, selenium and phosphorus. The term heteroaryl can include 5- or 6-membered heterocyclic rings, polycyclic heteroaromatic ring systems, and polycyclic heteroaromatic ring systems.

  As used herein, the term aralkyl is equivalent to the term arylalkyl, and is one or more unsubstituted or substituted monocyclic aromatic rings or non-bonded to an alkyl moiety. Means a substituted or substituted polycyclic aromatic ring; illustrative examples include benzyl, diphenylmethyl, trityl, 2-phenylethyl, 1-phenylethyl, 2-pyridylmethyl and 4,4′- Examples include, but are not limited to, dimethoxytrityl.

  One skilled in the art also recognizes that when components are grouped together in a common manner, such as in a Markush group, the present invention is not limited to the entire group enumerated as a whole, but the individual components of that group. Are easily recognized as well as all possible subgroups of the main group. Thus, for all purposes, the invention encompasses not only the main group, but also the main group that does not include one or more of the group members. The present invention also contemplates that any one or more of the group members are expressly excluded from the claimed invention.

  The term sugar includes monosaccharides, disaccharides and polysaccharides, each of which is optionally substituted. The term also includes sugars and deoxy sugars optionally substituted with amino, amide, urea, halogen, nitrile or azido groups. Illustrative examples include glucosamine, N-acetylglucosamine, desosamine, folosamine, sialic acid and the like.

  The process described herein is further illustrated by the following examples. The following examples are intended to be illustrative and therefore should not be construed as limiting and should not be construed as limiting in any manner.

CROSS REFERENCE TO RELATED APPLICATIONS This application is a US patent of US Provisional Patent Application No. 60 / 982,446 (filed Oct. 25, 2007, the disclosure of which is hereby incorporated by reference herein). Insist on the benefits of Article 119 (e) of the Act.

Example 1: Preparation of 2 ', 4 "-di-O-benzoyl-6-O-methylerythromycin A.
125 mL of ethyl acetate was added to 25 g of clarithromycin A. 26.5 g benzoic anhydride, 5.7 g 4-dimethylaminopyridine and 6.7 g triethylamine were added to the reaction mixture at 25-35 ° C. The reaction mixture was stirred at room temperature for about 70 hours. After completion of the reaction, ethyl acetate was distilled off to obtain the title compound.

Example 2: Preparation of 10,11-anhydro-2 ', 4 "-di-O-benzoyl-12-O-imidazolylcarbonyl-6-O-methylerythromycin A.
Dimethylformamide (DMF, 100 mL) is added to 2 ′, 4 ″ -di-O-benzoyl-6-O-methylerythromycin A at 25 ° C. to 35 ° C., followed by 1,8-diazabicyclo [5.4. 0] Undec-7-ene (DBU, 6.4 g) was added to the reaction mixture and stirred at room temperature. 1,1′-carbonyldiimidazole (CDI, 17 g) was added to the reaction mixture and stirred at room temperature until the reaction was complete. The title compound is isolated by adding water and collecting the resulting precipitate.

Example 3: 2 ', 4 "-di-O-benzoyl-11-N
Preparation of-(4-azidobutyl) -6-O-methylerythromycin A11,12-cyclic carbamate.
DMF (50 mL) was added to 10,11-anhydro-2 ′, 4 ″ -di-O-benzoyl-12-O-imidazolylcarbonyl-6-O-methylerythromycin A (10 g) at 25 ° C. to 35 ° C. It was. 4-Azidobutylamine (4.4 g) and DBU (1.5 g) were added to the reaction mixture, and then the reaction mixture was stirred at 25-35 ° C. until the reaction was complete. Thereafter, the reaction mixture was treated with cold water, and the resulting solid precipitate was collected. The title compound was obtained by treating the solid with dichloromethane followed by extraction and solvent removal. The molar equivalent ratio of 4-azidobutylamine to 10,11-anhydro-2 ′, 4 ″ -di-O-benzoyl-12-O-imidazolylcarbonyl-6-O-methylerythromycin A ranges from about 4: 1 to about It is arbitrarily chosen to be up to 3: 1. The molar ratio of DBU to 10,11-anhydro-2 ′, 4 ″ -di-O-benzoyl-12-O-imidazolylcarbonyl-6-O-methylerythromycin A is from about 1: 1 to about 0.75: It is arbitrarily chosen to be up to 1.

Example 4: Preparation of 11-N- (4-azidobutyl) -5- (2'-benzoyldesosaminyl) -3-hydroxy-6-O-methylerythronolide A11,12-cyclic carbamate.
Acetone (10 mL) is added to 2 ′, 4 ″ -di-O-benzoyl-11-N- (4-azidobutyl) -6-O-methylerythromycin A11,12-cyclic carbamate (5 g) to give a clear solution. The solution was obtained at 25 ° C to 35 ° C. Dilute HCl (10 mL) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and treated with sodium hydroxide solution to give the title compound.

Example 5: Preparation of 11-N- (4-azidobutyl) -5- (2'-benzoyldesosaminyl) -3-oxo-6-O-methylerythronolide A11,12-cyclic carbamate.
Dichloromethane (50 mL) was added to N-chlorosuccinimide (2 g) at room temperature under nitrogen and cooled to 0 ° C. Dimethyl sulfide (1.8 mL) was slowly added to the reaction mixture at 0 ° C. with stirring. 11-N- (4-azidobutyl) -5- (2′-benzoyldesosaminyl) -3-hydroxy-6-O-methylerythronolide A11,12-cyclic carbamate (5 g) dissolved in dichloromethane (20 mL) ) Was added dropwise to the reaction mixture at 0 ° C. with stirring. The reaction mixture was cooled to about −20 ° C. and a solution of triethylamine (4 mL) dissolved in dichloromethane (5 mL) was added to the reaction mixture and stirred for 30 minutes. After completion of the reaction, the reaction mixture was treated with saturated sodium bicarbonate solution and the organic layer was isolated. Distilling off the solvent gave the title compound. Additional reaction conditions are described by Plata et al. In Tetrahedron, 60 (2004), 10171-10180, the entire disclosure of which is incorporated herein by reference.

Example 5A: Preparation of 11-N- (4-azidobutyl) -5- (2'-benzoyldesosaminyl) -3-oxo-6-O-methylerythronolide A11,12-cyclic carbamate.
Of 11-N- (4-azidobutyl) -5- (2′-benzoyldesosaminyl) -3-hydroxy-6-O-methylerythronolide A11,12-cyclic carbamate (100 g, 0.1225 mol), Oxidation with Dess-Martin periodinane (170 g, 0.400 mol) was carried out in dichloromethane at 10-15 ° C. The reaction mixture was stirred at 20-25 ° C. for 2 hours. The reaction mixture was treated with 5% aqueous sodium hydroxide to quench the reaction. The organic layer was washed with water and saturated sodium chloride solution. The solvent was removed by distillation of the organic layer and the product was isolated from a mixture of diisopropyl ether and hexane. The separated solid was filtered and dried under vacuum at 30 ° C. to 35 ° C. to give the title compound. The molar equivalent ratio of Dess-Martin periodinane to 11-N- (4-azidobutyl) -5- (2′-benzoyldesosaminyl) -3-hydroxy-6-O-methylerythronolide A11,12-cyclic carbamate is Optionally from about 3.3: 1 to about 1.3: 1.

Example 6: 11-N- (4-azidobutyl) -5- (2'-benzoyldesosaminyl) -3-oxo-2-fluoro-6-O-methylerythronolide A, 11,12-cyclic carbamate Preparation.
11-N- (4-azidobutyl) -5- (2′-benzoyldesosaminyl) -3-oxo-6-O-methylerythronolide A11,12-cyclic carbamate (5 g) dissolved in tetrahydrofuran (400 mL) To the solution was added 7.3 mL potassium tert-butoxide, followed by 2 g N-fluorobenzenesulfonimide. After about 1 hour, the reaction was quenched by treating the reaction mixture with water followed by extraction with dichloromethane. The organic layer was separated and concentrated to give the title compound.

Example 6B: 11-N- (4-azidobutyl) -5- (2′-benzoyldesosaminyl) -3-oxo-2-fluoro-6-O-methylerythronolide A, 11,12-cyclic carbamate Preparation.
11-N- (4-azidobutyl) -5- (2′-benzoyldesosaminyl) -3-oxo-6-O-methylerythronolide A11,12-cyclic carbamate (100 g) dissolved in tetrahydrofuran (2200 mL) To the solution was added potassium tert-butoxide (28 g) at −20 ° C. to −5 ° C., followed by N-fluorobenzenesulfonimide (54 g). After about 1 hour, the reaction was quenched by treating the reaction mixture with 5% aqueous sodium bicarbonate. The separated organic layer was washed with water and saturated sodium chloride solution. The solvent was removed by distillation and the residue was crystallized from a mixture of isopropyl alcohol and water, filtered and dried under vacuum at 40 ° C. to 45 ° C. to give the title compound. M-equivalent of N-fluorobenzenesulfonimide to 11-N- (4-azidobutyl) -5- (2'-benzoyldesosaminyl) -3-oxo-6-O-methylerythronolide A11,12-cyclic carbamate The ratio is optionally from about 1.6: 1 to about 1.2: 1. The ratio of solvent (mL) to 11-N- (4-azidobutyl) -5- (2′-benzoyldesosaminyl) -3-oxo-6-O-methylerythronolide A11,12-cyclic carbamate is arbitrary And from about 22: 1 to about 17: 1.

Example 7: 11-N- (3-amino-phenyl-1-ylmethyl- [1,2,3] -triazol-1-yl] butyl) -5- (2′-benzoyldesosaminyl) -3- Oxo-2-fluoro-erythronolide A, 11,12-cyclic carbamate.
11-N- (3-amino-phenyl-1-ylmethyl- [1,2,3] -triazol-1-yl] butyl) -5- (2′-benzoyldesosaminyl) -3-oxo-2- Fluoro-6-O-methylerythronolide A, 11,12-cyclic carbamate (10 g), 3-ethynylphenylamine (2.11 g), copper iodide (0.3 g) and diisopropylethylamine (15.5 g). In addition to acetonitrile (200 mL), the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction was quenched by treating the reaction mixture with dilute HCl and extracted with dichloromethane. The organic layer was neutralized with bicarbonate solution, dried and concentrated to give the title compound.

Example 7B: 11-N- (3-amino-phenyl-1-ylmethyl- [1,2,3] -triazol-1-yl] butyl) -5-desosaminyl-3-oxo-2-fluoro-erythronolide A 11,12-cyclic carbamate.
11-N- (3-amino-phenyl-1-ylmethyl- [1,2,3] -triazol-1-yl] butyl) -5- (2′-benzoyldesosaminyl) -3-oxo-2- Fluoro-6-O-methylerythronolide A, 11,12-cyclic carbamate (100 g), 3-ethynylphenylamine (20 g), copper iodide (10 g) and diisopropylethylamine (155 g) are added to acetonitrile (600 mL). The mixture was stirred at 25 ° C to 30 ° C for 12 hours. 3-ethynylphenylamine vs. 11-N- (3-amino-phenyl-1-ylmethyl- [1,2,3] -triazol-1-yl] butyl) -5- (2′-benzoyldesosaminyl)- The molar equivalent ratio of 3-oxo-2-fluoro-6-O-methylerythronolide A, 11,12-cyclic carbamate is optionally from about 1.5: 1 to about 1.2: 1. After completion of the reaction, the reaction mixture was poured into dilute HCl and extracted with diisopropyl ether. The aqueous layer was extracted with dichloromethane. The dichloromethane layer was neutralized with aqueous sodium bicarbonate, dried (NaSO ₄ ) and concentrated to give the title compound. This material was added to methanol (600 mL) and the resulting mixture was heated at 50-55 ° C. for 12 hours. The solution was treated with activated carbon (10 g), filtered and concentrated under reduced pressure. The residue was dissolved in a mixture of water and EtOAc. The pH of the aqueous phase was adjusted to about 3.5. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (twice) followed by diisopropyl ether (twice). The resulting aqueous layer was added to aqueous ammonia (1000 mL of about 4% ammonia). The precipitated solid was collected by filtration, washed with water until the pH of the washing solution was about 7-8, and dried under reduced pressure to give the title compound. This material is optionally further purified by recrystallization from ethanol.

Example 8: 11-N- (3-Amino-phenyl-1-ylmethyl- [1,2,3] -triazol-1-yl] butyl) -5-desosaminyl-3-oxo-2-fluoro-erythronolide A 11,12-cyclic carbamate.
11-N- (3-amino-phenyl-1-ylmethyl- [1,2,3] -triazol-1-yl] butyl) -5- (2′-benzoyldesosaminyl) -3-oxo-2- Fluoro-erythronolide A, 11,12-cyclic carbamate (6 g) was dissolved in methanol (60 mL) and heated at reflux for 7 hours. After completion of the reaction, the reaction mixture was concentrated, diluted with diisopropyl ether (30 mL) and stirred at room temperature for 2 hours. The resulting solid was collected by filtration. This solid is optionally purified by precipitation, crystallization or chromatography. This material is optionally converted to a salt by adding an acid followed by precipitation of the resulting salt. Analysis of this material indicated that the title compound had a purity greater than 98%. By repeating Example 1 to Example 8, a 5 kg sample of the title compound of Example 8 was prepared. This large sample was found to contain less than about 0.1% aminophenylethyne or about 0.07% aminophenylethyne.

Example 9: 11-N- (3-Amino-phenyl-1-ylmethyl- [1,2,3] -triazol-1-yl] butyl) -5-desosaminyl-3-oxo-2-fluoro-erythronolide A Purification of 11,12-cyclic carbamate.
Florisil (21 kg) was packed into a column containing 63 L of ethyl acetate. 1.4 kg 11-N- (3-amino-phenyl-1-ylmethyl- [1,2,3] -triazol-1-yl] butyl) -5-desosaminyl-3-oxo-2-fluoro-erythronolide A , 11,12-cyclic carbamate dissolved in 14 L ethyl acetate and 0.7 L acetonitrile is passed through the column. Collect the eluate. Ethyl acetate (112 L) is passed through the column and the eluate is combined with the first fraction. This process is repeated four more times. The combined eluate was concentrated and the resulting residue was dissolved in 39 L of ethyl alcohol by heating to 50-55 ° C. Reduce the volume to about 22 L and cool to 25-30 ° C. The solution is stirred for 5-6 hours. The resulting solid is collected and washed with cold ethyl alcohol. The wet cake is dissolved in a solution of ethyl acetate / acetonitrile (15 L / 0.5 L per kg of wet cake) by heating to 40-45 ° C. Additional ethyl acetate (20 L per 1 kg wet cake) is added to the solution. This solution is passed through a Florisil column (15 kg per kg wet cake). Collect the eluate. The column is flushed with ethyl acetate (80 L / kg wet cake). Collect the eluate and combine with the first eluate. The combined eluates were concentrated and the resulting residue was dissolved in 39 L of ethyl alcohol by heating to 50-55 ° C. Reduce the volume to about 22 L and cool to 25-30 ° C. The solution is stirred for 5-6 hours. The resulting solid is collected and washed with cold ethyl alcohol. The filter cake is added to 50 L of water cooled to 10-15 ° C. Concentrated HCl (0.97 L) is added slowly at 10-15 ° C. to obtain a clear solution. The solution is filtered. The filtrate is slowly added to an aqueous ammonia solution (0.79 L of ammonia dissolved in 28 L of water) at 10 ° C to 25 ° C. The resulting mixture is stirred for 30 minutes and the solid is collected by centrifugation. This solid was dried at 45 ° C. to 50 ° C. until the water content was 1.5% or less.

  Example 9A: 11-N- (3-Amino-phenyl-1-ylmethyl- [1,2,3] -triazol-1-yl] butyl) -5-desosaminyl-3-oxo-2-fluoro-erythronolide A , 11,12-cyclic carbamate is optionally a second solvent in a solid or acidified mixture that precipitates from the solvent by dissolving the material in a minimum amount of solvent and adding acid to the resulting mixture. A solid that precipitates after the addition of is formed and purified.

Example 10: Preparation of 4-azido-butylamine.
1,4-Dibromobutane was dissolved in warm DMF and treated with sodium azide (3 molar equivalents). After the reaction was complete, the reaction mixture was diluted with water and 1,4-diazido-butane was extracted into methyl t-butyl ether. Triphenylphosphine (1.08 molar equivalent) was added to a solution of 1,4-diazido-butane. When the reaction was complete, the reaction mixture was diluted with 5% hydrochloric acid until hydrolysis was complete. The acidic aqueous layer was separated and made basic with dilute sodium hydroxide. The resulting product was extracted into methylene chloride. The organic layer was separated and concentrated under reduced pressure to give the title material. The preparation of 1,4-diazide-butane is optionally performed using a molar equivalent ratio to sodium azide of from about 1 to 3 to about 1 to 5. 1,4-diazido-butane is optionally reduced to 4-azido-butylamine by another reducing agent, such as sodium borohydride.

本比較例では、最初に、Ｃ−１２における活性化されているアシル化されたアリル性アルコールを４−アミノ−１−ブタノールと反応させ、続いて、側鎖ヒドロキシル基をトシルクロリドにより活性化し、最後に、ＮａＮ_３と反応させて、アジド側鎖を導入することによって、対応する側鎖アジドを調製する（一般的には、米国特許出願公開第２００６／０１００１６４号を参照のこと）。この比較例のプロセスでは、アジド基を側鎖に導入するために、少なくとも２つの工程が必ず必要とされる。 Comparative Example 1: For the preparation of macrolides, the process described by Romero et al. In Tetrahedron letters, 46: 1483-1487 (2005) is as follows:

In this comparative example, the activated acylated allylic alcohol at C-12 is first reacted with 4-amino-1-butanol, followed by activation of the side chain hydroxyl group with tosyl chloride, Finally, the corresponding side chain azide is prepared by reacting with NaN ₃ to introduce the azide side chain (see generally US Patent Application Publication No. 2006/0100164). In the process of this comparative example, in order to introduce an azide group into the side chain, at least two steps are necessarily required.

この場合、Ｈｕｉｓｇｅｎ反応が、保護されていないデソサミンに対して行われる。このような保護の欠如は、副生成物の形成をもたらすことが発見された。驚くべきことに、試薬の３−アミノフェニルエチンは、保護されていない最終生成物のトリアゾールから取り除くことが困難であることも、また発見された。さらに、対応する２’−アセチル保護された誘導体を、Ｈｕｉｓｇｅｎ環化で１，２，３−トリアゾールに変換することは、デソサミン糖から側鎖アニリンフラグメントのアミノ基へのアセチル転移を付随して引き起こし、このことは望まれない生成物形成をもたらし、それに対応して、収率の低下をもたらし、また、その後の精製工程の必要性をもたらすことが発見された。

Comparative Example 2: For the preparation of macrolides, the process described by Liang et al. And Romero et al. (Tetrahedron letters, 46: 1483-1487 (2005)) is as follows:

In this case, the Huisgen reaction is performed on unprotected desosamine. It has been discovered that this lack of protection results in the formation of by-products. Surprisingly, it has also been discovered that the reagent 3-aminophenylethyne is difficult to remove from the unprotected end product triazole. Furthermore, conversion of the corresponding 2'-acetyl protected derivative to 1,2,3-triazole by Huisgen cyclization concomitantly causes an acetyl transfer from the desosamine sugar to the amino group of the side chain aniline fragment. This has been found to result in unwanted product formation and correspondingly reduced yields and the need for subsequent purification steps.

Claims (13)

Compounds of the following formula:

(Where
R ^{1 is} a monosaccharide containing 2'-hydroxyl group is acylated with ^{R 1a, wherein, R 1a} is an sterically hindered acyl group;
A represents —CH ₂ —, —C (O) —, —C (O) O—, —C (O) NH—, —S (O) ₂ —, —S (O) ₂ NH—, or -C (O) NHS (O) _2- ;
B is — (CH ₂ ) _n —, where n is an integer from 0 to 10, or B is an unsaturated carbon chain of 2 to 10 carbons;
R ⁴ and R ⁵ are hydrogen, halogen, hydroxy, alkyl, arylalkyl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, acyl, acyloxy, sulfonyl, urea and carbamoyl (each of which is optionally substituted) Independently selected in each case from the group consisting of
V is —C (O) —, —C (═NR ¹¹ ) —, —CH (NR ¹² R ¹³ ) — or —N (R ¹⁴ ) CH ₂ —; where R ¹¹ is hydroxy or alkoxy R ¹² and R ¹³ are each independently hydrogen, hydroxy, alkyl, arylalkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, urea And R ¹⁴ is selected from the group consisting of hydrogen, hydroxy, alkyl, arylalkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, urea or carbamoyl Is;
W is hydrogen, F, Cl, Br, I or OH;
X is hydrogen; and Y is OR ⁷ ; wherein R ⁷ is hydrogen, monosaccharide, disaccharide, alkyl, aryl, heteroaryl, acyl, or —C (O) NR ⁸ R ⁹ Wherein R ⁸ and R ⁹ are each independently hydrogen, hydroxy, alkyl, arylalkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl, Or selected from urea or carbamoyl; or X and Y together with the carbon to which they are attached form C = O). The compound of claim 1 having the formula:

(Wherein R ^1a is a sterically hindered acyl group). The compound according to claim 1 or 2, wherein R ^1a is benzoyl. A compound of formula below having a purity greater than about 98%:

(In the formula, A represents —CH ₂ —, —C (O) —, —C (O) O—, —C (O) NH—, —S (O) ₂ —, —S (O) ₂ NH). — Or —C (O) NHS (O) ₂ —; B is — (CH ₂ ) _n —, where n is an integer from 0 to 10, or B Is an unsaturated carbon chain of 2 to 10 carbons).   5. The compound of claim 4, wherein the purity is greater than about 99%. Compounds of the following formula:

(Where
A represents —CH ₂ —, —C (O) —, —C (O) O—, —C (O) NH—, —S (O) ₂ —, —S (O) ₂ NH—, or -C (O) NHS (O) _2- ;
B is — (CH ₂ ) _n —, where n is an integer from 0 to 10 or B is an unsaturated carbon chain of 2 to 10 carbons)
A composition comprising less than about 0.15% aminophenylethyne as compared to the compound.   7. The composition of claim 6, comprising less than about 0.1% aminophenylethine compared to the compound.   The composition of claim 6 substantially free of aminophenylethyne. Compounds of the following formula:

(Where
A represents —CH ₂ —, —C (O) —, —C (O) O—, —C (O) NH—, —S (O) ₂ —, —S (O) ₂ NH—, or -C (O) NHS (O) _2- ; and
B is — (CH ₂ ) _n —, where n is an integer from 0 to 10 or B is an unsaturated carbon chain of 2 to 10 carbons)
A composition comprising less than about 2% acylaminophenyl as compared to the compound.   10. The composition of claim 9, comprising less than about 1% acylaminophenyl compared to the compound.   10. The composition of claim 9, comprising less than about 0.15% acylaminophenyl compared to the compound.   10. The composition of claim 9, comprising less than about 0.1% acylaminophenyl compared to the compound. 10. The composition of claim 9, substantially free of acylaminophenyl.